David T. Auble
( Email - Website )
Associate Professor
Department of Biochemistry and Molecular Genetics
PO Box 800733
Jordan Hall, 6213
Charlottesville, VA 22908-0733
Phone:434-243-2629
Fax:434-924-5069
Education and Experiences:
Case Western Reserve University: Ph.D., 1987;
Bowdoin College: B.A., 1981;
Postdoctoral Fellow, Hutchinson Cancer Research Center, 1990-1996;
Postdoctoral Fellow, Dartmouth Medical School, 1987-1990.
Interests:
We are interested in understanding the mechanisms of action and in vivo functions
of proteins belonging to a large evolutionarily-conserved family of nuclear ATPases
(called the Snf2/Swi2 family). Snf2/Swi2 family members are involved in transcriptional
regulation, DNA repair, recombination, and chromosome segregation, but how these
proteins work is not well understood, nor is it understood what roles most of
these proteins play in vivo. To better understand them, we are applying biochemical
and genetic approaches to define the activities of Snf2/Swi2-related proteins
in the yeast Saccharomyces cerevisiae.
Our work focuses on the Snf2/Swi2-related protein Mot1. Mot1 is an essential protein
that can regulate transcription by a remarkable mechanism: it disrupts TATA-binding
protein (TBP)-DNA complexes in an ATP-dependent manner. This disruption prevents
the formation of transcription complexes and can thereby inhibit transcription
in vitro. We are employing biochemical approaches using purified components to
determine how Mot1 recognizes TBP-DNA complexes and how ATP hydrolysis leads to
TBP-DNA complex dissociation. The activities of mutant Mot1 proteins and the effects
of other proteins that interact with TBP are also being explored. In vivo, the
effects of Mot1 on transcription appear to be complex. While some genes are repressed
by Mot1, others are apparently unaffected, or paradoxically, activated by Mot1.
Using a combination of genetic and molecular biological approaches, we are characterizing
genes that are regulated by Mot1 and we are developing strategies to determine
how Mot1 functions in vivo to give rise to complex patterns of gene expression.
Several of the yeast Snf2/Swi2 family members are involved in DNA repair, but
how they function is unknown. The biochemical activity of Mot1 suggests that they
disrupt or rearrange protein-DNA complexes as an obligate part of the repair process.
Using our knowledge of how Mot1 functions, genetic and biochemical experiments
are in progress to identify the protein targets of two of these repair proteins,
and biochemical approaches will be used to characterize their mechanisms of action.
Selected Projects:
MOLECULAR ANALYSIS OF A YEAST TRANSCRIPTIONAL REGULATOR
Molecular Analysis of a DNA Repair Complex
Molecular Analysis of a DNA Repair Complex
Molecular Analysis of a Yeast Transcriptional Regulator
Molecular Analysis of a Yeast Transcriptional Regulator
Postdoctoral Fellowship on Behalf of J.J. Smith
Selected Publications:
R.P. Darst, D. Wang, and D.T. Auble. (2001) Mot1-Catalyzed TBP-DNA Disruption: Uncoupling DNA Conformational Change and Role of Upstream DNA. EMBO J., 20:2048-2040
A. Dasgupta, R.P. Darst, K.J. Martin, C.A. Afshari, and D.T. Auble (2002). Mot1 activates and Represses Transcription by Direct, ATPase-Dependent Mechanisms. Proc. Nat. Acad. Sci. USA 99:2666-2671.
K.L. Ramsey, J. J. Smith, A. Dasgupta, N. Maqani, Patrick Grant and D.T. Auble. The NEF4 complex regulates Rad4 levels and utilizes Snf2/Swi2-related ATPase activity for nucleotide excision repair. Mol. Cell. Biol., 24:6362-6378, 2004.
A. Dasgupta, K.L. Ramsey, J.S. Smith and D.T. Auble. Sir Antagonist 1 (San1) is a Ubiquitin Ligase. J. Biol. Chem., 279: 26830-26838, 2004.
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